DOI: 10.4103/ijpvm.ijpvm_377_25 ISSN: 2008-7802

Genetic Variation of ApoE Gene in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Case-Control Studies

Vedika Gupta, Jnapika Devarapalli, Abhishek Mehan, Quoelee Biswas, Sophia John Bosco, Abhishek Hanumanpratap Singh Kshatri, Saahiti Kammadanam, Uma Chaudhry, Ayushi Gupta, Animesh Kumar Tiwari, R Keerthana, Mansi Trivedi, V. P. Akshay, N. S. Delna
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Abstract

Background and Aim:

Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disorder influenced by genetic and environmental factors. This systematic review and meta-analysis aimed to synthesize recent evidence on the association between ApoE gene polymorphisms and T2DM risk.

Methods:

This study adhered to PRISMA 2020 and MOOSE guidelines in reporting. Eligible studies were identified through comprehensive literature search in PubMed, Web of Science, and Google Scholar. Data were extracted independently by two reviewers, and study quality was assessed using the Newcastle-Ottawa Scale (NOS). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated under allelic, dominant, recessive, codominant, and additive (per-allele) genetic models using random-effects meta-analysis. Heterogeneity was assessed with I 2 and Cochran’s Q, publication bias with Egger’s test and funnel plots, and robustness with sensitivity and subgroup analyses. A Duval and Tweedie trim-and-fill method was applied where publication bias was suspected.

Results:

Eleven studies met inclusion criteria, comprising diverse populations from East Asia, the Middle East, South Asia, Africa, and Latin America. In the additive model, a total of 16,685 alleles (7,065 from T2DM cases and 9,620 from controls) were analyzed. The ε4 allele was significantly associated with increased T2DM risk (random-effects OR = 1.25, 95% CI: 1.05–1.48, P = 0.016; fixed-effect OR = 1.30, 95% CI: 1.20–1.42, P < 0.0001). The dominant model (E4 carriers vs non-carriers) showed a similar association (random-effects OR = 1.29, 95% CI: 1.03–1.62). No significant effect was observed in the recessive (E4/E4 vs. others; OR = 1.13, 95% CI: 0.73–1.75) or codominant (E4/E4 vs. E3/E3; OR = 1.20, 95% CI: 0.79–1.82) models. The E3/E4 heterozygote was associated with increased risk (random-effects OR = 1.41, 95% CI: 1.06–1.86). Subgroup analyses indicated stronger associations among Middle Eastern/North African and East Asian populations, with minimal or absent risk in African and Hispanic/Latino cohorts. Genotyping method was also a significant source of heterogeneity. Evidence of publication bias was limited in the main model; however, trim-and-fill analysis indicated possible small-study effects in the additive model.

Conclusions:

This synthesis provides strong evidence that the ApoE ε4 allele is a genetic risk factor for T2DM, under all models. While findings remained robust after adjustment for potential publication bias, further large-scale, multiethnic studies are required to clarify the exact magnitude of risk and to evaluate the integration of ApoE polymorphism testing into clinical practice for risk stratification.

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